title: Synbindin in extracellular signal-regulated protein kinase spatial regulation and gastric cancer aggressiveness.
abstract: BACKGROUND
  The molecular mechanisms that control the aggressiveness of gastric cancer (GC) remain poorly defined. Here we show that synbindin contributes to the aggressiveness of GC by activating extracellular signal-regulated protein kinase (ERK) signaling on the Golgi apparatus.
  
  
  METHODS
  Expression of synbindin was examined in normal gastric mucosa (n = 44), intestinal metaplastic gastric mucosa (n = 66), and GC tissues (n=52), and the biological effects of synbindin on tumor growth and ERK signaling were detected in cultured cells, nude mice, and human tissue samples. The interaction between synbindin and mitogen-activated protein kinase kinase (MEK1)/ERK was determined by immunofluorescence and fluorescence resonance energy transfer assays. The transactivation of synbindin by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) was detected using luciferase reporter assay and chromatin immunoprecipitation.
  
  
  RESULTS
  High expression of synbindin was associated with larger tumor size (120.8 vs 44.8 cm(3); P = .01), advanced tumor node metastasis (TNM) stage (P = .003), and shorter patient survival (hazard ratio = 1.51; 95% confidence interval [CI] = 1.01 to 2.27; P = .046). Synbindin promotes cell proliferation and invasion by activating ERK2 on the Golgi apparatus, and synbindin is directly transactivated by NF-κB. Synbindin expression level was statistically significantly higher in human GCs with activated ERK2 than those with low ERK2 activity (intensity score of 11.5, 95% CI = 10.4 to 12.4 vs intensity score of 4.6, 95% CI 3.9 to 5.3; P < .001). Targeting synbindin in xenograft tumors decreased ERK2 phosphorylation and statistically significantly reduced tumor volume (451.2mm(3), 95% CI = 328.3 to 574.1 vs 726.1mm(3), 95% CI = 544.2 to 908.2; P = .01).
  
  
  CONCLUSIONS
  Synbindin contributes to malignant phenotypes of GC by activating ERK on the Golgi, and synbindin is a potential biomarker and therapeutic target for GC.
authors.affiliation: Affiliations of authors: State Key Laboratory for Oncogenes and Related Genes, Shanghai, China (XK, JQ, L-SC, Y-CW, J-LW, HC, Y-RW, S-LZ, JH, Y-XC, JX, J-YF); Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Institute of Digestive Disease, Shanghai Jiao-Tong University School of Medicine, Shanghai, China (XK, JQ, L-SC, Y-CW, J-LW, HC, Y-RW, S-LZ, JH, Y-XC, JX, J-YF); Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Shanghai, China (XK, JQ, L-SC, Y-CW, J-LW, HC, Y-RW, S-LZ, JH, Y-XC, JX, J-YF); Department of Surgery, University of Michigan, Ann Arbor, MI (WZ).
authors.forename: Xuan
authors.initials: X
authors.lastname: Kong
authors.forename: Jin
authors.initials: J
authors.lastname: Qian
authors.forename: Li-Sha
authors.initials: LS
authors.lastname: Chen
authors.forename: Ying-Chao
authors.initials: YC
authors.lastname: Wang
authors.forename: Ji-Lin
authors.initials: JL
authors.lastname: Wang
authors.forename: Haoyan
authors.initials: H
authors.lastname: Chen
authors.forename: Yu-Rong
authors.initials: YR
authors.lastname: Weng
authors.forename: Shu-Liang
authors.initials: SL
authors.lastname: Zhao
authors.forename: Jie
authors.initials: J
authors.lastname: Hong
authors.forename: Ying-Xuan
authors.initials: YX
authors.lastname: Chen
authors.forename: Weiping
authors.initials: W
authors.lastname: Zou
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.forename: Jing-Yuan
authors.initials: JY
authors.lastname: Fang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D031541:Fluorescence Resonance Energy Transfer; D005455:Fluorescent Antibody Technique; D005753:Gastric Mucosa / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006056:Golgi Apparatus / Q000201:enzymology / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D053208:Kaplan-Meier Estimate; D008156:Luciferases; D049408:Luminescent Agents; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D016017:Odds Ratio; D010766:Phosphorylation; D040081:Protein Array Analysis; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D015533:Transcriptional Activation; D015854:Up-Regulation; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D049408:Luminescent Agents; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; C534479:TRAPPC4 protein, human; C415482:Trappc4 protein, mouse; D033921:Vesicular Transport Proteins; D008156:Luciferases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048369:MAP Kinase Kinase 1